High levels of cyclic di-GMP in Klebsiella pneumoniae attenuate virulence in the lung

ABSTRACT The bacterial second messenger bis-(3′-5′)-cyclic dimeric GMP (c-di-GMP) has been shown to influence the expression of virulence factors in certain pathogenic bacteria, but little is known about its activity in the increasingly antibiotic-resistant pathogen Klebsiella pneumoniae . Here, the expression in K. pneumoniae of a heterologous diguanylate cyclase increased the bacterial c-di-GMP concentration and attenuated pathogenesis in murine pneumonia. This attenuation remained evident in mice lacking the c-di-GMP sensor STING, indicating that the high c-di-GMP concentration exerted its influence not on host responses but on bacterial physiology. While serum resistance and capsule expression were unaffected by the increased c-di-GMP concentration, both type 3 and type 1 pili were strongly upregulated. Importantly, attenuation of K. pneumoniae virulence by high c-di-GMP levels was abrogated when type 1 pilus expression was silenced. We conclude that increased type 1 piliation may hamper K. pneumoniae virulence in the respiratory tract and that c-di-GMP signaling represents a potential therapeutic target for antibiotic-resistant K. pneumoniae in this niche. </jats:p

Sling Complications

https://digitalscholarship.unlv.edu/wrin_briefs/1003/thumbnail.jp

Surgeon Volume

https://digitalscholarship.unlv.edu/wrin_briefs/1002/thumbnail.jp

TGFβ1 orchestrates renal fibrosis following Escherichia coli pyelonephritis

Renal scarring after pyelonephritis is linked to long-term health risks for hypertension and chronic kidney disease. Androgen exposure increases susceptibility to, and severity of, uropathogenic Escherichia coli (UPEC) pyelonephritis and resultant scarring in both male and female mice, while anti-androgen therapy is protective against severe urinary tract infection (UTI) in these models. This work employed androgenized female C57BL/6 mice to elucidate the molecular mechanisms of post-infectious renal fibrosis and to determine how these pathways are altered by the presence of androgens. We found that elevated circulating testosterone levels primed the kidney for fibrosis by increasing local production of TGFβ1 before the initiation of UTI, altering the ratio of transcription factors Smad2 and Smad3 and increasing the presence of mesenchymal stem cell (MSC)-like cells and Gli1 + activated myofibroblasts, the cells primarily responsible for deposition of scar components. Increased production of TGFβ1 and aberrations in Smad2:Smad3 were maintained throughout the course of infection in the presence of androgen, correlating with renal scarring that was not observed in non-androgenized female mice. Pharmacologic inhibition of TGFβ1 signaling blunted myofibroblast activation. We conclude that renal fibrosis after pyelonephritis is exacerbated by the presence of androgens and involves activation of the TGFβ1 signaling cascade, leading to increases in cortical populations of MSC-like cells and the Gli1 + activated myofibroblasts that are responsible for scarring

Information Effects in Multi-Unit Dutch Auctions

We design a multi-unit descending-price (Dutch) auction mechanism that has applications for resource allocation and pricing problems. We address specific auction design choices by theoretically and experimentally determining optimal information disclosure along two dimensions. Bidders are either informed of the number of bidders in the auction, or know that it is one of two possible sizes; they also either know the number of units remaining for sale or are unaware of how many units have been taken by other bidders. We find that revealing group size decreases bids, and therefore revenue, if units remaining are not shown. When group size is unknown the price also falls if the number of units remaining is revealed. The most efficient and largest revenue outcome occurs when bidders are not provided information on either group size or units remaining. These laboratory results conform to some directional predictions from our theory, although overbidding is common

IDENTIFICATION OF POTENTIAL TARGETS OF THE GRR1P SCF UBIQUITIN LIGASE IN FUNGI

The opportunistic human pathogen Candida albicans causes both superficial and life-threatening systemic infections and is a leading cause of fungal disease in immunocompromised individuals.  C. albicans can grow in different cell shapes, or morphologies, including yeast-like cells and a variety of filamentous forms, such as true hyphae and pseudohyphae.   Yeast, hyphae and pseudohyphae have been observed at the sites of Candida infection and there is strong evidence that morphogenesis, the transition between yeast and filamentous growth forms, is essential for virulence. Several studies have implicated ubiquitin-dependent proteolysis in the regulation of morphogenesis, yet the mechanism by which this pathway does so is largely unknown.  Previously, we have shown that deletion of the GRR1 gene results in the constitutive formation of filamentous growth forms.  The Grr1 protein is a component of an SCF ubiquitin ligase system that selectively targets proteins for degradation.  Thus, the loss of Grr1-mediated proteolysis presumably leads to the aberrant accumulation, and inappropriate activity, of a protein or proteins that induce filamentous growth.  The spectrum of proteins targeted for degradation by Grr1 is not known.  The goal of this project is to identify Grr1 targets in Saccharomyces cerevisiae, an experimentally tractable model system for pathogenic fungi.  We are using a novel proteomics-based approach to isolate and characterize proteins that are ubiquitinated in a Grr1-dependent fashion. The successful identification of Grr1p targets will be important for developing a working model of the pathways involved in the yeast to filamentous growth transition in pathogenic fungi

BH3I-1 DERIVATIVES INHIBIT THE FILAMENTOUS GROWTH OF THE CEA10 STRAIN OF ASPERGILLUS FUMIGATUS

Recent and exciting advances in medical therapies for cancer and organ failures have greatly extended the life span of afflicted patients. However, these therapies often place the patient at risk for potentially lethal fungal infections. As the number of immunocompromised patients continues to rise, there has been an increase in associated opportunistic fungal infections. Treatment options for invasive mycoses caused by Candida albicans and Aspergillus fumigatus are surprisingly limited. A. fumigatus is the most common Aspergillus species associated with invasive pulmonary aspergillosis, accounting for over 60% of cases. Aspergillus grows as a filamentous mold with true hyphae originating from the germination of asexual conidia.  A. fumigatus is not a dimorphic fungi as is the case with C. albicans, however, as both grow in hyphal form it seems possible that small molecules that inhibit the transition of C. albicans budded cells to hyphal growth (often referred to as the germination of blastoconidia) may also inhibit the germination of Aspergillus conidia. We tested BH3I-1 and derivatives against A. fumigatus strain CEA10 in YPD media. BH3I-1 and five of the derivatives inhibited at a 200?M concentration based on general observation via microscopy as well as eleven showing promising inhibition at possible different concentrations. Out of these inhibiting molecules, seven also shown inhibition within the prior C. albicans assay. We are currently employing a micro-plate reader to obtain quantitative levels of inhibition with increasing concentrations of molecule. Molecule 54 at the 300?M concentration showed similar inhibition to that of BH3I-1 at the same concentration

Perceptions of Adolescent Pregnancy Among Teenage Girls in Rakai, Uganda.

The leading causes of death and disability among Ugandan female adolescents aged 15 to 19 years are pregnancy complications, unsafe abortions, and childbirth. Despite these statistics, our understanding of how girls perceive adolescent pregnancy is limited. This qualitative study explored the social and contextual factors shaping the perceptions of adolescent pregnancy and childbirth among a sample of 12 currently pregnant and 14 never pregnant girls living in the rural Rakai District of Uganda. Interviews were conducted to elicit perceived risk factors for pregnancy, associated community attitudes, and personal opinions on adolescent pregnancy. Findings indicate that notions of adolescent pregnancy are primarily influenced by perceptions of control over getting pregnant and readiness for childbearing. Premarital pregnancy was perceived as negative whereas postmarital pregnancy was regarded as positive. Greater understanding of the individual and contextual factors influencing perceptions can aid in development of salient, culturally appropriate policies and programs to mitigate unintended adolescent pregnancies

07291 Abstracts Collection -- Scientific Visualization

From 15.07. to 20.07.07, the Dagstuhl Seminar 07291 ``Scientific Visualization\u27\u27 was held in the International Conference and Research Center (IBFI),Schloss Dagstuhl. During the seminar, several participants presented their current research, and ongoing work and open problems were discussed. Abstracts of the presentations given during the seminar as well as abstracts of seminar results and ideas are put together in this paper. The first section describes the seminar topics and goals in general. Links to extended abstracts or full papers are provided, if available